Benz [b] indolo [2, 3-d] thiopyrylium compounds and processes for their production



United States Patent 3,388,133 BENZ[b]INDOL0[2,3 d]THIOPYRYLIUM COM-PGUNDS AND PROCESSES FOR THEIR PRODUCTION Thomas E. Young, Bethlehem,Pa., and Peter H. Scott,

Guilford, Conn., assignors to Warner-Lambert Pharmaceutical Company,Morris Plains, N.J., a corporation of Delaware No Drawing.Continuation-impart of application Ser. No. 457,860, May 21, 1965. Thisapplication May 23, 1966, Ser. No. 551,931

14 Claims. (Cl. 260-3269) ABSTRACT OF THE DISCLOSURE This inventionrelates to benz[b]indo1[2,3-d]thiopyrilium compounds of the formula:

wherein R, R and R can be the same or different, and are selected fromhydrogen, hydroxy, nitro, lower alkyl of 1 to 4 carbon atoms, loweralkoxy of 1 to 4 carbon atoms, and halogen; R is hydrogen, lower alkylof l to 4 carbon atoms or phenyl; and X is perchlorate or halide.

These compounds are useful as anti-bacterial and antifungal agents.

This application is a continuation-in-part of application Ser. No.457,860, filed May 21, 1965 for Benz[b]indolo [2,3-d1thiopyryliumCompounds and Process for Their Production, and now abandoned.

This invention relates to benz[b]indolo[2,3-d]thiopyry-lium compounds,to intermediate compounds useful for preparing them, and to processesfor their preparation. More particularly, the present invention relatesto a new class of compounds having the following formula:

wherein R, R and R can be the same or different, and are selected fromhydrogen, hydroxy, nitro, lower alkyl of 1 to 4 carbon atoms, e.g.methyl, ethyl, propyl, isopropyl, butyl, etc., lower alkoxy of 1 to 4carbon atoms, and halogen; R is hydrogen, lower alkyl of 1 to 4 carbonatoms or phenyl; and X is perchlorate or halide.

The benz[b]indolo[2,3-d1thiopyrylium compounds of formula I are usefulas antibacterial and antifungal agents, particularly against grampositive bacteria, e.g. Staphylococcus aureus, etc. and fungi. e.g.Candida albicans, etc.

The compounds of Formula I can be mixed with pharmaceutical adjuvants,and the resulting mixtures formed 3,388,133 Patented June 11, 1968 intosuitable dosage forms for topical and otic administration.

Topical ointment bases that can be employed with the compounds ofFormula I are those standard in the pharmaceutical compounding art, e.g.those having a base composed of one or more of the following: animalfats, animal waxes, essential oils, hydrogenated oils, lanolin, oliveoil, paraffins, etc. Examples of the above include wool alcohols, woolfat either alone or mixed with lard or paraffin, hydrogenated palmkernel oil, hydrogenated castor oil, etc. Additionally, oil-in-water andWater-in-oil bases described in the United States Pharmacopeia can alsobe used. Hardening agents such as beeswax can be incorporated in theabove.

The compounds of Formula I are employed in a therapeutically effectiveamount in the above ointment bases. They can be applied to the broken orunbroken skin of the animal body, and water soluble bases can also beused for otic application.

Also, a therapeutically effective amount of a compound of Formula I canbe used in a talcum powder base for use as a topical dusting powder.What constitutes a therapeutically effective amount of the compounds ofFormula I is dependent on various factors such as the particular baseemployed, the nature and site of the infection, etc. Generally, amountsranging from about 0.1 to about 5.0%, eg, about 1%, in the aboveointment and powder bases are advantageously employed, althoughquantities above and below these amounts can also be employed and arewithin the scope of the instant invention.

The compounds of Formula I are prepared by first reducing abenzenesulfonyl chloride compound of Formula II below with zinc andsulfuric acid to give the corresponding thiophenol compound IIIaccording to the following reaction scheme:

R msol II III wherein R has the meaning given above for Formula I.Thereafter, the compound of Formula III is reacted with a compound ofFormula IV, such as fi-chloropropionic acid, in basic solution to givethe corresponding phenylmercaptopropionic acid of Formula V according tothe following reaction:

C O OH R YCHRaCHgCOOH R IV CiHI CHR:

SH \s/ III V wherein R and R have the meaning given above and Y ischlorine or bromine. The phenylmercaptopropionic acid of Formula V isthen treated with sulfuric acid to effect cyclization and the formationof the corresponding thiochroman-4-one VI as follows:

V VI

The thiochroman-4-one (VI) is then reacted with a phenylhydrazinecompound VII in an acetic acid reaction medium to give compound VIIIaccording to the following reaction scheme:

l R l 5 Rv-GN-NH: R 011300211 VI VII l a 10 R, I S

l R VIII 2 wherein R, R R and R have the meanings given above.Alternately, the reaction may proceed as follows:

H R f R; -NNH2 CHtoHg s R3 CHsCDzH VI v11 3 3 onion M M: l m Q l N IXVIII wherein the R groups are as previously defined. Theindolo[3,2-c]thiochromene reaction product of Formula VIII is thenreacted with a suitable perchlorate such as trityl perchlorate toprepare the corresponding benz[b] indolo[2,3-d]thiopyrylium perchloratecompound by the following reaction scheme:

The benz[b]indolo[2,3-d]thiopyrylium perchlorate compound of Formula Iais then reacted with ammonia followed by a hydrohalic acid conversion togive a halide salt:

R1 3 0104 NH;

Ia R

3 R1 HXl R1 l 1 N I I X Ib wherein X represents halogen.

Alternatively, the corresponding halide may be formed by reacting theprepared perchlorate with an alkali metal halide such. as potassiumhalide according to the following reaction scheme:

Ia Ib When a 6-phenyl substituted ben.z[b]indolo[2,3-d]thiopyryliumperchlorate is desired, an alternate method of preparing this compoundis to react compound Ia wherein R is hydrogen with a Grignard reagentsuch as phenyl magnesium bromide, followed by further treatment withtrityl perchlorate as follows:

Is wherein Rq is phenyl.

As used throughout the specification, the terms halogen and halide areto be understood to mean the atoms of chlorine, bromine, fluorine, andiodine.

The practice of the present invention is further illustrated by thefollowing examples:

Example 1.--Benz [b] indolo [2,3-d] thiopyrylium perchlorate To a 500ml. three-neck round bottom flask equipped with a stirrer and a droppingfunnel having a vapor bypass is added 3.00 g. ofindolo[3,2-c]thiochromene [A. K. Kiang and F. G. Mann J. Chem. S0c.,1909 (1951)] and 100 ml. of glacial acetic acid. The system is purgedwith purified nitrogen after which the flask is warmed sufficiently todissolve the thiochromene. To the resulting solution is added drop-wiseand with continuous stirring 3.75 g. (0.0110 mole) of trityl perchlorate[K A. Hoffman and H. Kimmreuther, Ben, 42, 4865 (1909)] dissolved in 250ml. of acetic acid. Addition of the trityl perchlorate requires twohours, during which time the flask is heated to keep the solution warmalthough well below reflux tern- *erature. When about one-fourth of thetrityl perchlorate has been added to the system a glistening orangeprecipitate begins to appear. After the addition of trityl perchlorateis completed, the suspension is stirred without heating for two morehours after which it is filtered while still slightly warm. Therecovered precipitate, after being dried in vacuo over phosphoruspentoxide and potassium hydroxide, is found to weigh 1.37 g. and isfound to have a M.P. of 266-269 decomp. (darkening at 240). A secondfiltration taken after the filtrate is allowed to stand overnight,furnishes an additional 0.33 g. (M.P. 265-268 decomp.).Recrystallization of the precipitate from acetic acid gives fine yellowneedles of benz[b]indolo[2,3-d] thiopyrylium perchlorate, M.P. 273275(decomp.).

Analysis for C I I ClNO S.Calcd.: C, 53.65; H, 3.00; N, 4.17. Found: C,53.74; H, 3.18; N, 4.41.

Example 2.-Benz [b]indolo [2,3-d] thiopyryliurn chloride The precursor,benzib]indolo[2,3-d]thiopyran is prepared as follows: Ammonia gas isbubbled for one hour through a well stirred suspension of 2:11 g. (6.29millimoles) of benz[ b]indolo[2,3-d]thiopyrylium perchlorate (preparedin Example 1 in 75 ml. of dry benzene. The mixture is then filtered, andthe precipitate washed with fresh benzene after which the volume of thefiltrate is reduced to ml. on a steam bath. Cyclohexane is added slowlyto the hot solution until a precipitate begins to form, after which thesolution is cooled overnight in a refrigerator to complete theprecipitation. Filtration yields 1.33 g. (90%) of orange product havinga M.P. 167-170. Recrystallization from benzene-cyclohexane, followed bysublimation at 131136/ 0.015 provides analytically purebenz[b]indolo[2,3-d]thi0pyran (M.P. 168170).

Analysis for C H N-S.Calcd.: C, 76.65; H, 3.85; N, 5.91; S, 13.63.Found: C, 76.64; H, 3.71; N, 5.91; S, 13.50.

Gaseous hydrogen chloride is bubbled for fifteen minutes through asolution of 1.00 g. (4.26 millimoles) of benz[b]indolo[2,3-d]thiopyranin dry benzene. The resulting precipitate is collected by filtration anddried in a vacuum desiccator over potassium hydroxide. The yield is 1.16g. (100% On recrystallization from glacial acetic acid, small yellowneedles of benz[b]indolo[2,3-d]thiopyrylium chloride, which darken above250 and gradually decompose above 295 are recovered.

Analysis for C H ClNS.Calcd.: C, 66,29; H, 3.71; Cl, 13.05; N, 5.15; S,11.80. Found: C, 66.13; H, 3.84; Cl, 13.10; N, 5.10; S, 11.55.

Example 3.Benz [b]indolo [2,3-d] thiopyrylium iodide To a solution of1.00 g. (2.98 millimoles) of benz[b] indolo[2,3-d]thiopyryliumperchlorate (prepared as in Example 1) in 75 ml. of nitromethane is aded5.0 g. of potassium iodide, and the mixture is stirred for fifteenminutes, after which it is heated to boiling and filtered while hot. Thecooled filtrate yields 0.68 g. (63%) of orange needles which darkenabove 205 and slowly decompose above 245. Three recrystallizations fromnitromethane produce deep orange needles of benz[b]indolo[2,3-d1thiopyrylium iodide, which have about the same decompositionpoint as the unrecrystallized product.

Analysis for C H INS.C-alcd.: C. 49.61; H, 2.78; I, 34.94. Found: C,49.69; H, 2.79; I, 34.20.

Example 4.2-methylbenz [b] indolo [2,3-d1thiopyrylium perchlorate Theintermediate 2-methylindolo[3,2-c]thiochromene is prepared by thefollowing procedure: To a solution of 34.17 g. (0.192 mole) of6-methylthiochroman-4-one [R Arndt, W. Flemming, E. Seho'lz, and V.Lowensohn Ber., 56, 1269 (1923)] in 200 m1. of methanol are added 19.4nil. (0.194 mole) of phenylhydrazine and 0.5 ml. of glacial acetic'acid. The solution is heated briefly at reflux temperature on a steambath, after which it is allowed to stand overnight while thephenylhydrazone precipitates. The solution is again heated to reflux,and after the phenylhyd-razone redissolves hydrogen chloride is bubbledthrough the well stirred refluxing solution for 30 minutes, followingwhich the solution is stirred for an additional 30 minutes at reflux.Upon cooling, a precipitate forms as a solid mass. This precipitate isbroken up, and then both the precipitate and solution are poured ontoice-water containing 65 ml. of 50% sodium hydroxide. The cold solutionis then stirred until the initially tarry precipitate nearly solidifies.After being collected by filtration, this solid is stirred with 300 ml.of warm concentrated ammonium hydroxide, washed thoroughly with waterand dried in vacuo over calcium chloride to give 45.55 g. of ayellow-orange solid having a M.P. of 168 with considerable priorsoftening. This crude product is then refluxed with 300 ml. of carbontetrachloride, which fails to d ssolve the entire sample. The portionwhich does not dissolve has a M.P. of 169175. Fractionalrecrystallization of this material from benzene gives a total of 8.88 g.having a M.P. of 173-177". The carbon tetrachloride solution on coolinggives a dark red solid, (M.P. -174), which is combined with the tailfractions of the above-described fractional recrystallization. Fractionrecrystallization yields an additional 6.75 g. (M.P. 172- 176). Thetotal yield of product is found to be about 32%. Final recrystallizationfrom benzene-cyclohexane gives 2-methylindolo[3,2-c]thiochromene as paleyellow crystals having a M.P. of 173-175".

Analysis for C H NS.Calcd.: C, 76.45; H, 5.21; N, 5.57. Found: C, 76.67;H, 5.50; N, 5.52.

Into a 200 ml. three neck round bottom flask equipped with a stirrer isplaced 8.48 g. (0.0338 mole) of the intermediateZ-methylindolo[3,2-c1thiochromeue and 100 ml. of glacial acetic acid. Asmall Erlenmyer flask contain ng 11.5 g. (0.0338 mole) of tritylperchlorate is joined to the round bottom flask by a short section ofGooch tubing, and the entire system charged with purified nitrogen,after which the acetic acid is warmed sufliciently to d'ssolve thethiochromene. As soon as the thiochromene is completely dissolved, thetrity-l perchlorate is added, in portions, to the acid solution. Ayellow precipitate forms almost immediately, and when all the tritylperchlorate is added, the solution is allowed to cool to roomtemperature, with continued stirring. The stirrer is then shut off, andthe reaction mixture permitted to stand overnight. The resultingprecipitate is collected by filtration, washed with glacial acetic acidand then anhydrous ether, and dried in vacuo over potassium hydroxide.The filtrate, on standing, yields a small amount of additionalprecipitate which is added to the original batch. The total yield is11.66 g. having a M.P. of 299 (decomp.). On recrystallization fromnitromethane, tiny, deep-yellow needles of pure2-methylbenz[b]indolo[2,3-d]thiopyrylium perchlorate having a M.P. of304-305, decomp. are recovered.

Analysis for C H ClNO S.-Calcd.: C, 54.94; H, 3.46; N, 4.00. Found: C,55.23; H, 3.74; N, 4.08.

7 Example 5.-2-methylbenz [b 1 indolo [2,3-d] thiopyrylium chlorideAmmonia gas is bubbled for ten minutes through a stirred slurry of 6.11g. (0.0175 mole) of Z-methylbenz [b]indolo[2,3-d]thiopyryliumperchlorate (prepared in Example 4) in 150 ml. of dry benzene. Themixture is allowed to stir an additional ten minutes; then it isfiltered, the salt cake washed with little benzene and the benzeneremoved in vacuo. The yellow precipitate is dissolved in 150 ml. offresh dry benzene and the mixture stirred while hydrogen chloride gas ispassed over the solution. After twenty minutes the reaction is completedand the resulting yellow precipitate is filtered, washed with a littlebenzene followed by dry ether. The product is then recrystallized fromglacial acetic acid and dried in vacuo at 135 for ten hours to yield4.82 g. (96%) of yellow crystals, M.P. darkening above 270, 281-284 dec.

Analysis for C H ClNS.Calcd.: C, 67.24; H, 4.23; CI, 12.41; S, 11.22.Found: C, 67.16; H, 4.48; Cl, 12.25; S, 11.18.

Example 6.-2-chlorobenz[b]indolo [2,3-d]thiopyrylium perchlorate Theintermediate 2-chloroindolo[3,2-c1thiochromene is prepared as follows:To a solution of 40.8 g. (0.205 mole) of 6-chlorothiochroman-4-one [F.Arndt. W. Flemming, E. Scholz, and V. Lowensohn, Ben, 56, 1269 (1923)]in 200 ml. of methanol is added 20.5 ml. (0.205 mole) of phenylhydrazineand 0.5 ml. of glacial acetic acid. The solution is heated briefly atreflux temperature on a steam bath, after which it is allowed to standuntil the phenylhydrazone precipitates. The solution is again heated toreflux, and after the phenylhydrazone partially redissolves, hydrogenchloride is bubbled through the wellstirred, refluxing solution for 30minutes, during which time a precipitate forms. The reaction mixture isthen allowed to stand overnight, following which it is poured ontoice-water containing 65 ml. of 50% sodium hydroxide. The resultingmixture is stirred for several hours and permitted to stand overnight toassure complete hydrolysis. Finally, the precipitate is collected byfiltration, washed thoroughly with water, and dried in vacuo overcalcium chloride to give 53.2]. g. of product having a M.P. of 140- 160with prior softening. Impurities are extracted from this precipitate byrefluxing in 100 ml. of carbon tetrachloride. The portion insoluble inthe carbon tetrachlo ride is then fractionally recrystallized frombenzene to yield a total of 30.93 g. (56%) of light tan product having aM.P. of 159-163. Three recrystallizations from benzene-cyclohexane giveanalytically pure 2-chloroindolo[3,2-c]thiochromene as white crystals(M.P. 162- 165).

Analysis for C H ClNS.-Calcd.: C, 66.29; H, 3.71; N, 5.16; Cl, 13.05.Found: C, 66.46; H, 3.96; N, 5.15; Cl, 12.89.

The intermediate 2-chloroindolo[3,2 -c]thiochromene (10.02 g. 0.0369mole) is reacted with an equimolar amount (12.65 g.) of tritylperchlorate under conditions identical with those described for theZ-methyl analog (Example 4). The reaction yields 12.28 g. of yellowmicrocrystals, M.P. 316-317" decomp., and upon allowing the filtrate tostand, an additional 0.49 g. of 2-chlorobenz[b]indolo[2,3-d]thiopyryliumperchlorate having a M.P. of 314 decomp. is obtained (total yield, 93%).

Analysis for C H Cl- NO S.Calcd.: C, 48.66; H, 2.45; N, 3.78. Found: C,48.74; H, 2.69; N, 3.82.

Example 7.--2-chlorobenz[b]indo1o [2,3 -d] thiopyrylium chloride Theintermediate 2 chlorobenz[b]indolo[2,3 dlthiopyran is prepared asfollows: Gaseous ammonia is bubbled for 30 minutes through awell-stirred suspension of 3.57 g. (0.00968 mole) of2-chlorobenz[b]indolo[2,3-d]- thiopyrylium perchlorate (prepared as inExample 5) in 8 100 5) in 100 ml. of chloroform. After being stirred foran additional hour, the resulting mixture is filtered, and theprecipitate washed once with chloroform. The original filtrate and thewashing are combined and evaporated to dryness at reduced pressure,yielding 2.49 g. of orange powder, having a. M.P. of 217-220".Recrystallization from benzene gives golden needles of 2-chlorobenz-[b]indolo[2,3-d] thiopyran having a M.P. of 2225-2245 Analysis for C HClNS.-Calcd.: C, 66.78; H, 2.99; N, 5.19; S, 11.89; Cl, 13.15. Found: C,66.74; H, 3.09; N, 5.16; S, 11.89; Cl, 12.97.

Gaseous hydrogen chloride is bubbled for fifteen minutes through asolution of 2.00 g. (7.42 millimoles) of the intermediate2-chlorobenz[b]indolo[2,3-d]thiopyran in ml. of chloroform. Theresulting precipitate is collected by filtration and dried in a vacuumdesiccator over potassium hydroxide. The yield is found to be 2.16 g.(95%). Two recrystallizations from glacial acetic acid gives smallbrownish-yellow needles of 2-chlorobenz[b]- indolo [2,3-d1thiopyryliumchloride which gradually darken and decompose above 250.

Analysis for C H Cl NS.-Calcd.: C, 58.83; H, 2.97; Cl, 23.16; N, 4.57;S, 10.47. Found: C, 58.98; H, 2.81; Cl, 23.20; N, 4.67; S, 10.16.

Example 8.-2-bromobenz [b] indolo [2,3-d] thiopyrylium perchlorate Theintermediate Z-bromoindolo[3,2-c1thiochromene is prepared as follows: Toa solution of 36.36 g. (0.149 mole) of 6-bromothiochroman-4-one[F.Arndt, W.'Flemming, E. Scholz, and V. Lowensohn, Ben, 56, 1269(1923)] in 200 ml. of methanol are added 15.5 ml. (0.155

mole) of phenylhydrazine and 0.5 ml. of glacial acetic acid. Thesolution is heated briefly at reflux temperature on a steam bath, afterwhich it is allowed to stand overnight while the phenylhydrazoneprecipitates. The solution is again heated to reflux, and after thephenylhydrazone partially redissolves, hydrogen chloride is bubbledthrough the well-stirred, refluxing solution for 30 minutes. The mixtureis then stirred for an additional 30 minutes, following which thehydrogen chloride is continued for another 30 minute interval. Themixture next is cooled and poured into about one liter of watercontaining 65 ml. of 50% sodium hydroxide. The resulting mixture isstirred for several hours and is then permitted to stand overnight toassure complete hydrolysis. Finally, the precipitate is collected byfiltration, washed thoroughly with water, and dried to give 47.08 g. ofcrude brown product. Impurities are extracted from the precipitate byrefluxing in 100 ml. of carbon tetrachloride. The portion insoluble inthe carbon tetrachloride is fractionally recrystallized from benzene,which yields 9.36 g. of pale tan product having a M.P. of 176-179, and2.76 g. having a M.P. of 172-176 (total yield 26% A lay-product ofapproximately 9 g. of a dark red solid insoluble in benzene is alsoobtained having a M.P. of 198-203 with prior softening.Recrystallization of the crude 2-bromoindolo[3,2 -c]thiochromene frombenzene-cyclohexane gives the pure compound as white crystals having aM.P. of 178-180.5.

Analysis for C H BrNS.-Calcd.: C, 56.97; H, 3.19; N, 4.43; Br, 25.27.Found: C, 57.45; H, 3.30; N, 4.38; Br, 24.12.

2-bromobenz[b]indolo[2,3-d1thiopyrylium perchlorate is prepared from theintermediate 2-bromoindolo-[3,2-c]

9 Analysis for C H BrClNO S.--Calcd.: C, 43.44; H, 2.19; N, 3.38. Found:C, 43.68; H, 2.48; N, 3.44.

Example 9.-8-methylbenz [b indolo [2,3-d] thiopyrylium perchlorate Theprecursor 8-methylindolo[3,2-c1thiochromene is prepared as follows: Amixture of 13.53 g. (0.0825 mole) of thiochroman-4-one [A. K. Kiang andF. G. Mann, J. Chem. Soc., 1909, (1951)] and 13.10 g. (0.0826 mole) ofp-tolylhydrazine hydrochloride in 150 ml. of glacial acetic acid isrefluxed with stirring overnight. The undissolved material is removed byhot filtration. The filtrate on cooling yields 12.22 g. (59%) of yellowcrystals, M.P. 178188. Successive recrystallization from chloroform thenfrom benzene-cyclohexane gives the pure product as small pale yellowplates having a M.P. of 190-193".

Analysis for C H NS.Calcd.: C, 76.45; H, 5.21; N, 5.57. Found: C, 76.68;H, 5.47; N, 5.49.

8-methylindolo[3,2-c]thiochromene, 12.27 g. (0.049 mole) and 16.8 g.(0.049 mole) of trityl perchlorate is allowed to react in 200 ml. ofglacial acetic acid as described for the 2-methyl analog (Example 4).The crude product is found to weigh 14.30 g. (84% yield) and has a M.Pof 307309 decomp. Recrystallization from nitromethane gives goldenneedles of pure 8-methylbenz[b]- indolo[2,3-d1thiopyrylium perchloratehaving a M.P. of 321-322 decomp.

Analysis for C I-l ClNO S.-Calcd.: C, 54.94; H, 3.46; N, 4.00. Found: C,54.95; H, 3.43; N, 4.05.

Example 10.8-methylbenz b] indolo [2,3-d] thiopyrylium chloride Ammoniais bubbled through a slurry of 6.25 g. (0.0179 mole) of8-methylbenz[b]indolo[2,3-d1thiopyrylium perchlorate, prepared inExample 9, in 150 ml. of chloroform for 40 minutes. The mixture is thenfiltered, and the precipitate washed with a little chloroform. Thecombined filtrate and washing, when rotary evaporated, yield 4.22 g.(94%) of orange-red solid, 8-methylbenz[b]- indolo[2,3-d]thiopyran, M.P.168-175". Several recrystallizations from benzene-cyclohexane giveorange needles, M.P. 181183.

Analysis for C H NS.Calcd.: C, 77.07; H, 4.45; N, 5.62; S, 12.86. Found:C, 76.97; H, 4.22; N, 5.50; S, 12.71.

Hydrogen chloride is bubbled through a solution of 2.15 g. (8.64millimoles) of 8-methylbenz[b]indolo- [2,3-d]thiopyran. A precipitateforms almost immediately. After ten minutes, the precipitate iscollected by filtration, washed with benzene and dried in vacuo overpotassium hydroxide. The yield of8-methylbenz[b]indolo[2,3-d]thiopyrylium chloride is 2.25 g. (91%), M.P.ca. 300 dec. with prior darkening. Three recrystallizations fromabsolute ethanol give an analytically pure sample, M. P. ca. 300 dec.darkening above 240.

Analysis for C H ClNS.Calcd.: C, 67.24; H, 4.23; Cl, 12.41; N, 4.90; S,11.22. Found: C, 67.26; H, 4.39; Cl, 12.25; N, 4.85; S, 11.06.

Example 11.11-methylbenz[b]indolo[2,3-d]thiopyrylium perchlorate Theintermediate 11-rnethylindolo[3,2-c]thiochromene is prepared as follows:A solution of 21.9 g. (0.133 mole) of thiochroman-4-one and 16.25 g.(0.133 mole) of 1- methyl-l-phenylhydrazine in 100 ml. of glacial aceticacid is refluxed overnight. A precipitate of nearly white needles formson cooling. The precipitate is found to weigh 17.50 g. (52%) and has aM.P. of 95-99. A portion recrystallized thrice from cyclohexane is foundto have a M.P. of 97.5-99.

Analysis for C H NS.-Calcd.: C, 76.45; H, 5.21; N, 5.57; S. 12.76.Found: C, 76.61; H, 5.46; N, 5.66; S, 12.68.

1l-methylindolo[3,2-c]thiochromene, 18.77 g. (0.0747 mole) and 24.6 g.(0.0717 mole) of trityl perchlorate are allowed to react in 150 ml. ofglacial acetic acid as described for the 2-methyl analog (Example 4).The crude product, which is collected by filtration, washed withanhydrous ether, and air dried, weighs 24.25 g. (97%). Recrystallizationof a portion from nitromethane gives yellow-green crystal of1l-methylbenz[b]indolo[2,3-d]- thiopyrylium perchlorate having a M.P. of311.5-312.5 decomp.

Analysis for C H ClNO S.Calcd.: C, 54.94; H, 3.46; N, 4.00. Found: C,55.11; H, 3.59; N, 3.95.

Example 12.--6-phenyl-1 l-methylbenz [b indolo [2,3-d]thiopyryliumperchlorate To a slurry of 900.7 mg. (2.58 millimoles) of 11-methylbenz[b]indolo[2,3 dlthiopyprylium perchlorate prepared by Example11 in 6 ml. of anhydrous ether is added dropwise an ethereal solution of2.9 millimoles of phenyl magnesium bromide. An exothermic reaction takesplace with the formation of a dark tarry product which partiallysolidifies when stirred for one hour. The mixture is then poured into anaqueous solution of ammonium sulfate, and the two liquid phases areseparated. A yellow insoluble residue (100 mg.) is retained with theaqueous phase. The residue and water layer are extracted 1 with 10 ml.of ether, which is then combined with the original solution. Evaporationof the dried (MgSO ether on a rotary evaporator yields 568.5 mg. of ayellow oil. When cooled to room temperature, this oil solidifies to aglass which crystallizes when triturated with warm acetic acid. Thissolid is dissolved in 25 ml. of acetic acid at 60, and to the stirredsolution is added dropwise 604.5 mg. (1.76 millimoles) of tritylperchlorate in 10 ml. of nitromethane. When the addition is com pleted,the solution is refluxed for eight minutes, after which it is allowed tostand overnight. The solvents are removed on a rotary evaporator, andthe residue triturated with ether. A yellow-green ether insoluble solid(644.2 mg, M.P. 218225 dec.) is collected by filtration. Onrecrystallization from acetic acid, 550.0 mg. (50% overall yield) ofproduct having a M.P. of 234- 237 partial dec. is recovered. A portionrecrystallized several more times from acetic acid gives greenish-yellowcrystals having a M.P. of 237241 partial dec.

Analysis for C H ClNO S.-Calcd.: C, 62.04; H, 3.79; Cl, 8.32; S, 7.53.Found: C, 61.77; H, 3.93; Cl, 8.41; S, 7.40.

Example 13.6-methylbenz[b]indolo [2,3-d]thio pyrylium perchlorate Astirred solution of 66.0 g. (0.60 mole) of thiophenol, 52.0 g. (0.60mole) of crotonic acid and 0.5 ml. of morpholine is heated slowly (ca.1.5 hours) to a solution temperature of 230. Once the temperature is at230, where it remains constant, the solution is heated for an additional20 minutes. The solution is then cooled and a small amount of unreactedthiophenol removed by distillation in vacuo. The crude acid is thencooled to room temperature and poured with stirring onto 640 ml. (ca.1180 g.) of precooled (10) concentrated sulfuric acid. After standingovernight at room temperature the solution is poured with stirring onto4 liters of crushed ice. The mixture is then extracted thrice with 300ml. portions of benzene; a red base soluble gum being benzene insoluble.The combined benzene extracts are washed with two 300 ml. portions of 5%bicarbonate solution then with 300 ml. of water, dried over magnesiumsulfate for 30 minutes, then filtered. The benzene is removed in vacuoand the remaining orange oil distilled through a modified Claisen headwith vacuum takeoff yielding 66.6 g. (62%) of yellow oil, B.P. 81- 90/0.15 mm. with some superheating. Attempted fractionation through afour-inch vigreux column gives 60.0 g. (57%) of material, B.P. startingat 80, mostly at 889l/0.08 mm. with a pot temperature of (Fractionationis unsuccessful since the oil is easily 11 superheated and superheatingis necessary to obtain a reasonable boiling rate.) The yellow oil is2-methyl thiochroman-4-one, and has a melting point of 17l9 (cooled inDry-Ice acetone) and 11 1.6097 lit. M.P. 18-19", 11, 1.6125

A solution of 17.8 g. (0.100 mole) of 2-methy1 thiochroman-4-one, 10.97g. (10.0 ml., 0.101 mole) of phenylhydrazine and two drops of glacialacetic acid in 50 ml. of absolute ethanol is refluxed for three hours.The solution becomes pale orange on heating. After standing overnight atroom temperature an oil, which cannot be induced to crystallize,separates. The mixture is then stirred and externally cooled whileanhydrous hydroge chloride gas is passed over the solution. After fivemin utes the whole mass solidifies so that the hydrogen chloride fiow isstopped, the solid broken up and the mixture refluxed for one hour.Hydrogen chloride is again passed over the solution for five minutes andrefluxing continued for another hour. The red mixture is then cooled inan ice-water bath and the resulting crop of yellow crystals collected,slurried with 10% sodium hydroxide solution, refiltered, washed wellwith water, then recrystallized from 250 ml. of benzene. The resultingprecipitate is collected, washed once with benzene, then petroleum etherand air dried yielding 10.0 g. (40%) of buff to pale yellow crystals,M.P. 188190. After two additional recrystallizations from benzene thematerial has a melting point of 189-191. A five ml. saturated benzenesolution is chromatographed on Fischer adsorption alumina and elutedwith benzene. The first 50 ml. (colorless) portion is evaporated to givean analytical sample of pale yellow crystals of6-1nethyl-6,1l-dihydrobenz[b]indolo[2,3-d]thiopyran, M.P. 189-191".

Analysis for C H NS.Calcd.: C, 76.45; H, 5.21; N, 5.57; 5, 12.76. Found:C, 76.31; H, 5.34; N, 5.52; S, 12.50.

In a three necked flask equipped with magnetic stirrer is placed 2.51 g.(0.010 mole) of 6-methyl-6,11-dihydrobenz[b]indolo[2,3-d]thiopyran and60 ml. of glacial acetic acid and the mixture heated to 105 C. under aflow of dry nitrogen. Trityl perchlorate, 3.43 g. (0.010 mole), is thenadded slowly from a small Erlenmeyer flask attached to the reactionflask by a piece of gooch tubing. A yellow precipitates forms almostimmediately and when all the trityl perchlorate is added the solution isallowed to cool to room temperature, stirring and the nitrogen flowstopped, and the reaction mixture allowed to stand overnight. Theprecipitate is then filtered, washed with a small amount of glacialacetic acid followed by dry ether and air dried yielding 3.40 g. (97%)of yellow product, M.P. black spots ca. 266 followed by slowdecomposition. Recrystallization from nitromethane gives 2.60 g. (75%)of 6-methylbenz[b]indolo[2,3-d]thiopyrylium perchlorate, M.P. slowdecomposition above 270.

Analysis for C H ClNO S.Calcd.: C, 54.94; H, 3.46; N, 4.00; S, 9.11.Found: C, 54.74; H, 3.68; N, 4.08; S, 8.93.

Example 14.6-methylbenz [b]indolo [2,3-d] thiopyrylium chloride Ammoniagas is bubbled through a stirred slurry of 6.17 g. (0.0178 mole) of6-methylbenz[b]indolo[2,3-d] thiopyrylium perchlorate in 150 ml. of drybenzene for three minutes. The reaction mixture is stirred for anadditional ten minutes, then filtered by suction. The salt cake is thenwashed twice, each time with ml. of warm benzene. The benzene solutionsare combined and the solvent removed in vacuo with a minimum of heating(preliminary isolation of the free base indicated that the compound isheat sensitive). The orange solid is then dissolved in 150 ml. of drybenzene and hydrogen chloride is passed over the stirred solution. Aprecipitate forms almost immediately and after ten minutes the hydrogenchloride flow is stopped, the slurry is stirred for an additionalminutes, then filtered. The lime-colored crys- N, 4.82; Cl, 12.35;S,11.02.

Example 15 .8-meth0xybenz[b] indolo [2,3-d] thiopyrylium perchlorate Asolution of 19.0 g. (0.138 mole) of p-methoxy phenylhydrazine, 22.6 g.(0.138 mole) of thiochromanone and ml. of glacial acetic acid arerefluxed overnight, the color of the mixture being dark brown. The nextmorning the solution is cooled, the pale orange crystals filtered andwashed with acetic acid until the filtrate is colorless. The yield,after drying in vacuo over potassium hydroxide, is 28.0 g. (76%), M.P.165-169. A sample recrystallized twice from methanol, once frombenzenecyclohexane, then sublimed twice at 150/ 0.025 mm. givesanalytically pure, pale tan crystals of 8-methoxy-6,11-dihydrobenz[b]indolo[2,3-d]thiopyran, M.P. 170.5 173 with shrinkingat 168.

Analysis for C H 'NOS.- Calcd.: C, 71.88; H, 4.90; S, 11.99. Found: C,72.07; H, 5.19; S, 11.84.

A slurry of 8-methoxy-6,1l-dihydrobenz[b]indolo[2,3- d] thiopyran (13.37g., 0.050 mole) in 150 ml. of glacial acetic acid is heated to under aflow of dry nitrogen. Trityl perchlorate (17.14 g., 0.050 mole) is thenadded in portions from a small Erlenmeyer flask attached to the reactionflask by a piece of gooch tubing; a red solid precipitates almostimmediately. When all the trityl perchlorate has been added the nitrogenflow is stopped and the mixture allowed to cool to room temperature withstirring. The brick red crystals are filtered and dried in vacuo at 90for two hours to yield 17.75 g. (97%) of crystals, M.P. 325 dec. withprior darkening. A 3.00 g. sample is recrystallized twice from 300 m1.portions of nitromethane to yield 0.93 g. of bright red needles ofS-methoxybenz [b]indolo[2,3-d1thiopyrylium perchlorate, M.P. 338- 340dec.

Analysis for C H C1NO S.-Calcd.: C, 52.54; H, 3.31; S, 8.77. Found: C,52.33; H, 3.20; S, 8.66.

Example 16.-8-methoxybenz[blindolo[2,3-d] thiopyrylium chloride Ammoniagas is bubbled for ten minutes through a stirred slurry of 6.09 g.(0.0166 mole) of 8-methoxybenz [b]indolo[2,3-dlthiopyrylium perchlorate,prepared in Example 15, in ml. of anhydrous benzene. The ammoniumperchlorate is filtered off, washed with a small amount of benzene andthe benzene solution evaporated to dryness in vacuo. The red free baseis then redissolved in 150 ml. of fresh dry benzene and stirred ashydrogen chloride gas is passed over the solution for 20 minutes. Thevery fine red crystals are filtered through sintered glass and dried invacuo at 90 for four hours to yield 3.85 g. (77%) of8-methoxybenz[b]indo1o[2,3d]thiopyrylium chloride, M.P. 264 -268 dec.,with prior shrinking. The sample when recrystallized from 500 ml. ofacetic acid gives 3.27 g. (67%) of red needles, M.P. slow decompositionabove 265, with spotting ca. 260.

Analysis for C H ClNOS.Calcd.: C, 64.01; H, 4.01; Cl, 11.75; S, 10.62.Found: C, 64.24; H, 4.12; Cl, 12.02; S, 10.39.

Example 17.2-nitrobenz[b]indo1o[2,3-dlthiopyrylium perchlorate Theprecursor, 6-nitrothiochroman-4-one phenylhydrazone, is prepared asfollows: To 5.84 g. (0.0279 mole) of 6-nitrothiochroman-4-one [V.Bellavita, Gazz, chim. ital., 70, 599 (1940)], stirred with 150 ml. ofboiling methanol, is added 2.9 ml. (0.029 mole) of phenylhydrazine andten drops of glacial acetic acid. After five minutes, the mixture iscooled to room temperature, then 13 allowed to stand for one day. Thered precipitate is collected by filtration and dried to give 7.55 g.(90%) of product which melts at 198-205". Three recrystallizations frommethanol gives the pure phenylhydrazone, M.P. 204.5-206.

Analysis for C H N O S. Calcd.: C, 60.19; H, 4.37; N, 14.04; S, 10.71.Found: C, 60.19; H, 4.42; -N, 13.97; S, 10.47.

The intermediate 2-nitroindolo[3,2-c]thiochromene is then prepared fromthe foregoing phenylhydrazone by the following procedure: Hydrogenchloride gas is bubbled for two hours through a slurry of 2.50 g. (8.36millimoles) of 6-nitrothiochroman-4-one phenylhydrazone in 100 ml. ofboiling methanol. The mixture is heated under reflux for sixteen morehours, after which it is poured into one liter of ice-water. The aqueousmixture is made basic with 50% sodium hydroxide, and the resulting solidproduct collected by filtration. After being washed with water and airdried, the rust colored indolo compound weighs 2.22 g. (94%) and doesnot melt but gradually darkens above 200. Several recrystallizationsfrom nitromethane affords pure 2-nitroindolo[3,2-c]thiochromene, whichdarkens above 250.

Analysis for C H N O S.Calcd.: C, 63.81; H, 3.57; N, 9.92; S, 11.36.Found: C, 63.63; H, 3.76; N, 9.72; S. 11.05.

The intermediate 2 nitroindolo[3,2-c]thiochromene (1.08 g., 3.83millimoles) is reacted with 1.33 g. (3.88 millimoles) of tritylperchlorate under conditions identical with those described for the2-methyl analog (Example 4). The reaction yields 1.36 g. (93/) ofproduct, M.P. 316 decomp. Recrystallization from nitromethane affordsbrown-yellow crystals of pure 2-nitrobenz[b]indolo[2,3-d] thiopyryliumperchlorate, M.P. 321322 decomp.

Analysis for C H ClN O S.Calcd.: C, 47.32; H, 2.38; N, 7.36. Found: C,47.30; H, 2.66; N, 7.24.

EXAMPLE 18 An ointment is prepared for topical use from the followingingredients:

Parts by 'weight Benz[b]indolo[2,3-d]thiopyrylium perchlorate 10Hydrogenated castor oil 60 Hard parafiin 160 Soft paraflim- 170 Liquidparaffin 600 wherein R, R and R are the same or different and areselected from hydrogen, hydroxy, nitro, lower alkyl, lower alkoxy, andhalogen; R is hydrogen, lower :alkyl of 1 to 4 carbon atoms, or phenyl;and X is halide or perchlorate.

2. The compound of claim 1 which is 2-methylbenz [*b] indolo[2,3-d1thiopyrylium perchlorate.

3. The compound of claim 1 which is 2-bromobenz [b] indolo[2,3-d]thiopyrylium perchlorate.

4. The compound of claim 1 which is ll-methylbenz[b]indolo[2,3-d]thiopyrylium perchlorate.

5. The compound of claim 1 which is6-phenyl-11-methylbenz[b]indolo[2,3-d]thiopyrylium perchlorate.

6. A compound having the (formula:

wherein R and R are the same or different and are selected fromhydrogen, hydroxy, nitro, lower alkyl of 1 to 4 carbon atoms, loweralkoxy of 1 to 4 carbon atoms, and halogen, and R is hydrogen, loweralkyl of 1 to 4 carbon atoms or phenyl.

7. The compound of claim 6 which is benz[b]indolo [2,3-d]thiopyran.

8. The compound of claim 6 which is 2-chlorobenz[b]indolo[2,3-d]thiopyran.

9. A method for preparing a compound of claim 1 wherein X is halidewhich comprises:

(A) reacting a compound of the formula:

wherein R, R and R have the meanings given in claim 1 with a hydrohalicacid to form a compound of the formula:

lS X1 R, R and R are hydrogen.

15 16 14. A compound of claim 1 wherein R is methyl and Kiang et a1.:Jour. Chem. Soc., 1951, pp. 19094914. R, R and R are hydrogen.Luttringhaus et a1.: Naturwissenschaften, v01. 44

(1957 584-585. References Cited pp 7 Cagniant et a1.: Compt. Rend, vol.243, No. 6 (1961), 5 NICHOLAS S. RIZZO, Primary Examiner. pp. 1702-04.

Fieser et a1.: Adv. Org. Chem. (Reinhold Pub.) (1961), NARCAVAGE Examinep. 704.

